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Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury.

Kilbaugh, Todd J; Karlsson, Michael LU ; Duhaime, Ann-Christine; Hansson, Magnus LU ; Elmer, Eskil LU and Margulies, Susan S (2015) In Mitochondrion
Abstract
Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain's response differs from the adult, especially in diffuse non-impact TBI. We perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal... (More)
Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain's response differs from the adult, especially in diffuse non-impact TBI. We perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4O) respiration was increased in both hippocampal and cortical tissue, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24h. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. In addition, mitochondrial respiration 24h after diffuse TBI that varies by location within the brain. Finally, we conclude that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Mitochondrion
publisher
Elsevier
external identifiers
  • pmid:26549476
  • scopus:84947969500
  • wos:000370768100003
ISSN
1567-7249
DOI
10.1016/j.mito.2015.11.001
language
English
LU publication?
yes
id
f33165f1-2679-4b35-b762-d20670d24173 (old id 8239994)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26549476?dopt=Abstract
date added to LUP
2015-12-03 15:39:17
date last changed
2017-01-01 07:34:22
@article{f33165f1-2679-4b35-b762-d20670d24173,
  abstract     = {Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain's response differs from the adult, especially in diffuse non-impact TBI. We perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4O) respiration was increased in both hippocampal and cortical tissue, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24h. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. In addition, mitochondrial respiration 24h after diffuse TBI that varies by location within the brain. Finally, we conclude that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain.},
  author       = {Kilbaugh, Todd J and Karlsson, Michael and Duhaime, Ann-Christine and Hansson, Magnus and Elmer, Eskil and Margulies, Susan S},
  issn         = {1567-7249},
  language     = {eng},
  month        = {11},
  publisher    = {Elsevier},
  series       = {Mitochondrion},
  title        = {Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury.},
  url          = {http://dx.doi.org/10.1016/j.mito.2015.11.001},
  year         = {2015},
}